Pyrido(2, 3d) pyrimidines

ABSTRACT

WHEREIN R2 represents a pyridyl, chloropyridyl, sulfonamidopyridyl, sulfonamidochloropyridyl, phenyl, trifluoromethylphenyl, chlorophenyl, nitrophenyl, sulfonamidophenyl, sulfonamidochlorophenyl, methylchlorophenyl, aminophenyl, alkylaminophenyl, dialkylaminophenyl, acylaminophenyl, alkoxyphenyl or pyrimidyl radical; R1, when R3 is nul, represents hydrogen - provided that R2 is different from a 3&#39;&#39;-pyridyl radical - a halogen, a substituted or not linear or branched alkyl radical of 1 to 5 carbon atoms, a linear or branched lower alkenyl radical comprising only one carbon-carbon double bond, an alkoxy radical, an alkylthio radical, an amino radical provided that R2 is different from a 3&#39;&#39;-pyridyl radical, a mono- or disubstituted amino radical, a carbohydrazide, a carbo-N2-alkylhydrazide, a hydrazino radical, a N2-alkylhydrazino radical, a mono- or disubstituted carboxamide, a substituted or not carboxyl radical, a heterocyclic radical, such as morpholino, piperidino, piperazino, which is substituted or not, a sulfonic radical a substituted or not sulfonamide, or an oxo or thio group when R3 is hydrogen (except when R1 is an oxo group and R2 is phenyl), an hydroxy radical, a linear or branched alkyl radical, substituted or not, a trifluoromethyl radical, a linear or branched alkenyl radical, a cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, pyridyl, pyrimidyl, substituted or not benzyl, substituted or not phenyl radical. Said compounds are particularly useful as neuroleptic and tranquillizing agents.   Substituted derivatives of pyrido (2,3d) pyrimidine, having the general formula:

United States Osselaere et al.

atent 1 [111 3,873,545 I [451 Mar. 25, 1975 l 5 4 l PYRIDO(2 ,3d} A RXRIMIPINE S [75] Inventors: Jean P. Osselaere, Alleur; Charles L. Lapiere, Tongeren, both of Belgium [22] Filed: Oct. 3, 1972 [21] Appl. No.: 294,650

[30] Foreign Application Priority Data Sept. 14. 1972 Luxembourg 66085 Oct. 5, l97l Luxembourg 64010 [52] US. Cl ..260/256.5 R, 260/247.l,

260/2472 R, 260/2472 A, 260/2475 B,

[51] Int. Cl C07d 51/46 [58] Field of Search...260 247.5 B 256,4 F, 256.5 R

[56] References Cited OTHER PUBLICATIONS Bayer, Acta Chim. Acad. Sci. Hung, 48(4), 353363 1966 lQied e t al., Justus Liebigs Ann. Chem. 707, 250-255 (1967). Taylor et al., J. Am. Chem. Soc. 80, 427431 (1958). Taylor et al., J. Org. Chem. 26, 4967-4974 (1961).

Primary E.\'aminerG. Thomas Todd Attorney, Agent. or FirmWigman &' Cohen l l ABSTRACT Substituted derivatives of pyrido [2,3d] pyrimidine, having the general formula:

wherein R represents a pyridyl, chloropyridyl, sulfonamidopyridyl, sulfonamidochloropyridyl, phenyl, trifluoromethylphenyl, chlorophenyl, nitrophenyl, sulfonamidophenyl, sulfonamidochlorophenyl, methylchlorophenyl, aminophenyl, alkylaminophenyl, dialkylaminophenyl, acylaminophenyl, alkoxyphenyl or pyrimidyl radical; R when R, is nul, represents hydrogen provided that R is different from a 3'- pyridyl radical a halogen, a substituted or not linear or branched alkyl radical of l to 5 carbon atoms, a linear or branched lower alkenyl radical comprising only one carbon-carbon double bond, an alkoxy radical, an alkylthio radical, an amino radical provided that R is different from a 3-pyridyl radical, a monoor disubstituted amino radical, a carbohydrazide, a carbo-N alkylhydrazide, a hydrazino radical, a N alkylhydrazino radical, a monoor disubstituted carboxamide,'a substituted or not carboxyl radical, a heterocyclic radical, such as morpholino, piperidino, piperazino, which is substituted or not, a sulfonic radical a substituted or not sulfonamide, or an oxo or thio group when R is hydrogen (except when R is an oxo group and R is phenyl),'an hydroxy radical, a linear or branched alkyl radical, substituted or not, a trifluoromethyl radical, a linear or branched alkenyl radical. a cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, pyridyl, pyrimidyl, substituted or not benzyl, substituted or not phenyl radical.

Said compounds are particularly useful as neuroleptic and tranquillizing agents.

15 Claims, No Drawings 1 IPQQQQ vP RUY"12. 1.5 .1

This invention relates to new derivatives of pyrido [2,3d] pyrimidine, as well as to the preparation and therapeutical use thereof.

The new pyrido [2,3d] pyrimidines of the invention are represented by the general formula I:

wherein R, represents a pyridyl, chloropyridyl, sulfonamidopyridyl, sulfonamidochloropyridyl, phenyl, trifluoromethylphenyl, chlorophenyl, nitrophenyl, sulfonamidophenyl, sulfonamidochlorophenyl, methylchlorophenyl, aminophenyl, alkylaminophenyl, dialkylaminophenyl, acylaminophenyl, alkoxyphenyl or pyrimidyl radical.

When R, is a monovalent radical, R is nu] and in this case R, represents hydrogen (provided that R is different from a 3'-pyridyl radical), a halogen, a substituted or not, linear or branched alkyl radical of l to 5 carbon atoms, a linear or branched lower alkenyl radical com-. prising only one double carbon-carbon bond, an alkoxy radical, an alkylthio radical, an amino radical (provided that R is different from a 3'-pyridyl radical), a monoor disubstituted amino radical, a carbohydrazide, a carbo-N -alkylhydrazide, a hydrazino radical, a N -alkylhydrazino radical, a monoor disubstituted carboxamide, a substituted or not carboxyl radical, a heterocyclic radical, such as morpholino, piperidino, pyrrolidino, piperazino, which is substituted or not, a sulfonic radical or a substituted or not sulfonamide.

When R, is an 0x0 or thio group, R is hydrogen (except when R, is an oxo group and R is a phenyl radical), a hydroxy, substituted or not linear or branched alkyl, trifluoromethyl, linear or branched alkenyl, cyclopentyl, cyclopentenyl, eyclohexyl, cyclohexenyl, pyridyl, pyrimidyl, substituted or not benzyl, substituted or not phenyl radical.

When R, and R represent an alkyl group, the latter can be substituted by amino, alkylamino, dialkylamino, halogen, hydroxy, trifluoromethyl groups or a heterocyclic group, such as morpholino, piperidino, pyrrolidino, piperazino ro N-alkylpiperaz'ino.

When R, represents an amino radical, the latter can be substituted by alkyl, dialkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, branched or not lower acyl, aminoacyl, alkylaminoacyl or dialkylaminoacyl groups.

When R, represents a carboxamide radical, the latter can be substituted by alkyl, dialkyl, aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl groups.

When R, represents a carboxyl radical, the latter can be substituted by alkyl, aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl groups.

When R, represents a sulfonamide radical, the latter can be substituted by alkyl, dialkyl or acyl groups. R, can also be a piperidino-, pyrrolidino-, morpholino-, piperazinoor N-alkylpiperazinosulfonamide.

This is just the same when R represents a sulfonamide radical.

, latter can be substituted by chloro or trifluoromethyl groups in position 2, 3 or 4 on this aromatic ring,

The terms alkyl, alkenyl or lower acyl radical are used as meaning linear or branched radicals having no more than 5 carbon atoms.

The compounds according to the invention can include one or more asymmetrical centers and in this connection they can exist as several stereoisomeric forms or mixtures thereof, also according to the invention.

The new compounds obtained can be used as therapeutical agents either alone or in combination with other therapeutical agents having similar or different effects.

The new derivatives of formula I can be obtained by cyclising substances of formula II: 1

wherein R, has the hereinbefore mentioned meaning and R, corresponds to following radicals: carboxyl, carboxylate ester or carboxamide, such as defined for R,, or alkoxy and hydrogen.

Said substances of formula II are new per se and are also within the scope of the present invention.

Derivatives of general formula II, wherein R, is an alkoxy radical, can advantageously be prepared by concoQAlkyla on acid chlorides of formula R COCl or mixed anhydrides of formula R COOCOOC H R having the previously mentioned meaning.

One can operate in solution in hydrocarbons, such as benzene for example, or in dioxan, or in any other solvent which can be considered as being inert in the reaction conditions, in presence of at least 1 mol of a tertiary amine, such as for example triethylamine.

Temperatures between room temperature and boiling temperature of the solvent are used during periods varying between 1 and several hours.

A variant consists ofcarrying out the condensation of one mol of alkyl aminonicotinate on one mol of acid chloride R COOCI in an amount of pyridine which is equal to 3 times the weight of ester used. In this case. the mixture is brought to boiling by refluxing during 2 to 3 hours.

According to the invention. derivatives of general formula II are cyclised by heating in presence of a solution of ammoniac or of an aliphatic or aromatic primary amine.

As solvent one may use lower alcohols, hydrocarbons, such as benzene, toluene or xylenes, pyridine, the amine itself when the latter is liquid, or any other solvent which can be considered as being consistent with operating conditions.

One operates at temperatures between 80C and 150C, under reflux or in a closed vessel, and the heating is maintained for several hours, generally 4 to 6 hours or more.

A large excess of amine is always used: at least mols per l mol of the derivative ll used.

In the case R in above formula ll is an alkyl radical and R is such as described previously, pyrido [2,3d] pyrimidines of formula I are obtained, wherein R is an oxo radical and R is one of the previously described radicals or hydrogen.

When R, is hydrogen or an alkyl radical, a carboxyl or carboxylate radical or a carboxamide radical, such as described for R, and R and such as previously defined, derivatives of formula I are obtained, wherein R is hydrogen or an alkyl, carboxyl or carboxamide radical.

Derivatives of general formula I wherein R corresponds to an oxo group can also be prepared by condensing an acid chloride of general formula R COCl, with R corresponding to the previously given definition, on 2-aminonicotinamide of general formula III:

\ CONH-R3 N NH wherein R is such as already described.

This is carried out for example by refluxing in the presence of pyridine for a period varying between 4 and 48 hours, by using one mol of derivative Ill and 2 mols of acid chloride R COCl in an amount of pyridine equal to ten-fold the weight of amide used.

One may also use one mol of derivative lll dissolved in ten-fold its weight of pyridine and one mol of acid chloride R COCl. The mixture is boiled by refluxing for 2 hours, then 0.9 mol of phosphorus oxychloride is added and thereafter the heating is extended for the time required.

This invention has also for its object the preparation of derivatives of general formula 1 which cannot be directly obtained by cyclisation but by substitution on derivatives 1.

Thus the reaction of substituted pyrido [2,3d] pyrimidines of formula I wherein R is an oxo radical and R is hydrogen, with phosphorus oxychloride by refluxing allows to obtain 2-substituted 4-chloropyrido [2,3d] pyrimidines. Oxo derivative is refluxed in 10- fold its weight of phosphorus oxychloride till total dissolution.

According to another process of the invention, said chlorinated derivatives are easily transformed into amino or hydrazino derivatives, substituted or not, by action of ammoniac, primary or secondary amines, cyclic amines, hydrazine or an alkylhydrazine. The reaction is carried out in alcoholic solution or the reagent itself is used as solvent. One uses temperatures between 50 and 100C, under reflux or in a closed vessel, for a period varrying between one and several hours. The

substituents so introduced are such as defined for R From 2-substituted 4-chloropyrido [2,3d] pyrimidines, it is also possible according to the invention to obtain the 4-alkoxy and 4-alkylthio derivatives previously described by reaction with corresponding alkaline alcoholates or thioalcoholates.

According to another preparation process, the reaction of potassium hydrogenosulfide on 4-chloro derivatives of the invention transforms the latter into derivatives of formula l wherein R, is a thio radical and R is hydrogen.

One part of the 4-chloro derivative is refluxed in a solution consisting of 20 parts of ethanol, 20 parts of water and 5 parts of potassium hydrogenosulfide for about 1 hour.

According to another process of the invention, the 4-oxo derivatives of formula 1 can be transformed into 4-thio derivatives of formula I by action of phosphorus pentasulfide under reflux in pyridine.

One part of 4-oxo derivative, l,l part of phosphorus pentasulfide and 5 parts of pyridine are used and one keeps boiling by refluxing for 4 hours.

Another process of the invention has for its object I the preparation of [2,3d] pyrimidines of formula I wherein R, is an oxo radical and R is such as previously described.

According to this process, the pyrido [2,3] pyrimidines of formula I wherein R is an oxo radical and R is hydrogen form, by action of alkaline alcoholates, alkaline salts .of formula V:

N-Me

wherein Me is an alkali metal.

Said salts are prepared by action an equimolecular amount of alkaline alcoholate in alcoholic solution on the oxo derivative. Primary alcohols of l to 4 carbon atoms are used. The alcoholic solution of alkaline salt is immediately reacted with an equimolecular amount of a halogenated derivative of formula R X, with R having the meaning already given and X being a halogen, such as Cl, Br or I, and thus corresponding 4-oxo derivatives are obtained.

Another process of the invention relates to the preparation of pyrido [2,3d] pyrimidines of formula I wherein R is an oxo radical and R is a 3-nitrophenyl, 3 '-sulfonamidophenyl or 3 -sulfonamido-4- chlorophenyl radical, which can also be obtained by nitration or sulfonation of the corresponding phenyl or chlorophenyl derivative.

The nitration is carried out in sulfonitric medium at a temperature of C for l to 4 hours. One part of the 4-oxo derivative, 3 parts of concentrated sulfuric acid and 3 parts of fuming nitric acid are used.

The sulfonation is carried out by reacting 10 parts of chlorosulfonic acid and one part of 4-oxo derivative. The solution is heated for 12 hours at 220C. The sulfonic acid chloride so obtained is treated with an aqueous solution of ammoniac or a primary, secondary or cyclic amine and thus the corresponding sulfonamide is obtained.

The products according to the invention can be puri- -Continued fied by a suitable process, such as fractlonal distillation,

Theoretlcal, 7: C:6l.99; H:4.83; N:l5.49 crystalllsatlon, counter-current dlstrlbutlon and ad- Found (36,35; H.511; N15 sorption.

Other details and features of the invention, which do 5 not limit the sco e thereof, are iven hereinafter b p g y EXAMPLE 4 means of examples of preparation of several compounds of formula I and formula 11, as well as with Ethyl 2-(3'-nitrobenzoyl)aminonicotinate pharmacological results of various of said compounds. This substance was prepared according to Process 2 EXAMPLE 1 of Example 1, but by using metanitrobenzoyl chloride instead ofb z lchl 'd .M It t: 126C. Ethyl 2-benzoylaminonicotinate en y on e 6 mg pom Process l To a solutlon 0f 17 g of ethyl Z-ammomcotmate ln 1 Elemental analysis for ClsHmNaOs 175 ml of benzene, ml of triethylamine are added Theoretical, 057.14; H:4.15; N 1333 under stirring and then 14 g of benzoyl chloride. The Found 056-94; i437? N solution is stirred for 24 hours at room temperature,

the mixture is then evaporated under reduced pressure,

the dry residue is taken up with water and extracted EXAMPLE 5 with chloroform after verification of the aqueous phase alkalinity. The chloroform extract is dehydrated on calcium Chloride, filtered and concentrated undel- Obtained from metachlorobenzoic acid chloride acduced pressure. The evaporation residue is recrystalconging to Process 2 of Example Melting Point! lised from petrolein l00140C. Yield: 74%. Melting 25 131 point: 106C.

Ethyl 2-(3-chlorobenzoyl)aminonicotinate Process 2 A mixture of 42 g of ethyl 2-aminonicotinate, of 140 Elemental analysis f CHHMNZOKC] ml of anhydrous pyridine and of 37 g of benzoyl chlo- Theoretical :5 H2 3 N1 1? ride is brought to boiling by refluxing for 2 to 3 hours. Found c5932; H2462" N907 The cooled solution is evaporated to dryness under reduced pressure and the evaporation residue is taken up with water. After having verified the alkalinity of the X PLE 6 aqueous phase, extraction is made with chloroform. Ethyl 2 (3l sulfonamido 4l chlorobenzoyl) The extraction liquid, dehydrated on calcium chloride, aminonicotinate is evaporated to dryness under reduced pressure and the residue, recrystallised from petrolein 100l40C, To h acid chloride P 'f from 9 g of has a melting point of 106C Yield. 70 to 80%. fonamldo-4-chlorobenzolc acld, 150 cc of anhydrous dioxane, 10 ml of triethylamine and 9 g of ethyl 2- aminonicotinate are added. The solution is cold stirred fro 18 hours. The mixture is filtered, dry evaporated Elemental analysis for ls H under reduced pressure and the evaporation residue is 2822122: recrystallised from a mixture ethanol-water. Melting point: 198C.

EXAMPLE 2 v Elemental analysis for C H N O SCl Ethyl 2-nlcotlnoylamlnonlconnate 1 Theoretical, 046.94, H:3.65; N:10.95; Cl:9.26 Found, C:47.12; H:3.84; N:11.07; Cl:9.42 Thls substance was prepared accordlng to Process 2 of Example 1. but by using nicotinic acid chloride instead of benzoyl chloride. Melting point: 96C.

EXAMPLE 7 Ethyl Z-picolinoylaminonicotinate Elemental analysis for C HiiNB i 12.3 g of picolic acid are dissolved in 100 cc of dioxflfiga i f {15212512121533 ane for analysis. 14 ml of triethylamine are added. The solution so obtained is cooled to 0C and 10 ml of freshly redistilled ethyl chloroformate are added under stirring. Stirring is still carried out for 30 minutes at EXAMPLE 3 room temperature. To the reaction mixture. 18.3 g of Ethyl gq i i l i i mi ethyl 2-aminonicotinate are added. one agitates for 30 minutes at room temperature and then one heats under stirring at C for 30 minutes. One allows to stand at room temperature overnight. The solution is then evaporated to dryness, the residue is taken up with water and extracted with chloroform after verification of the alkalinity of the aqueous phase. The extraction liquid Elemental analysis for C H N O is dehydrated on calcium chloride, filtered and evapo- This product is prepared according to Process 2 of Example 1 but by using isonicotinic acid chloride instead of benzoyl chloride. Melting point: 117C.

rated to dryness under reduced pressure. The residue is recrystallised from petrolein ll40C. Yield: about 60%. Melting point: 138C.

Elemental analysis for C H N O Theoretical, 72 C:6l.99; H:4.83; N:l5.49 Found. 7a C:6l.85; H:4.9l; N:l5.63

EXAMPLE 8 2-(3-Pyridyl)-3,4-dihydro-pyrido [2,3d] pyrimidine-4-one A mixture of 13 g of ethyl 2-aminonicotinate, of 40 ml of anhydrous pyridine and of l 1.5 g of nicotinic acid chloride is brought to boiling by refluxing for 2 to 3 hours. The cooled solution is evaporated to dryness under reduced pressure and the evaporation residue is taken up with water. After having verified the alkalinity of the aqueous phase, extraction is made with chloroform. The extraction liquid having been dehydrated on calcium chloride is evaporated to dryness under reduced pressure and the residue obtained, namely ethyl 2-nicotinoylaminonicotinate, is recrystallised from petroleum l00l40C. 8.] g of said recrystallised ethyl 2-nicotinoylaminonicotinate are then heated with 80 ml of anhydrous methanol saturated with ammoniac in an autoclave at 120C for 4 hours. After cooling, CH OH is distilled under reduced pressure. After recrystallisation from methanol and desolvatation in vacuum-drier at 120C for 4 hours, 6 g of the abovementioned compound are obtained. Melting point: 295.5C.

Elemental analysis for C, H, N O

Theoretical, 7r C:64.28; H2360; N:24.98

Found. 7r C:64.l l; H:3.67; N:24.87

EXAMPLE 9 Elemental analysis for C H N O Theoretical, 72 :C:64.28; H:3.6(); N:24.98 :C:64.53; H:3.70; Nt24r83 Found. 7:

EXAMPLE l0 2-(2-Pyridyl-3,4-dihydro-pyrido [2,3d] pyrimidine-4-one Obtained according to the process of Example 8, by using ethyl 2-picolinoylaminonicotinate. Substance recrystallised from methanol. Melting point: 299.5C.

Elemental analysis for C,- .H,.N,O Theoretical. /1 C6428; H:3.6(l; N:24.98

Found, 2064.22; H:3.82; N:25.l2

Prepared according to the process of Example 8 but by using ethyl 2-(3-chlorobenzoyl) aminonicotinate instead of ethyl 2-nic0tinoylaminonicotinate. Substance recrystallised from a mixture of methanol-water.

Melting point: 268C Elemental analysis for C H Theoretical, "/0 C 0.6 :C 0.6

:6 Found. :6

EXAMPLE l2 2-(4'-Chlorophenyl)-3,4-dihydro-pyrido [2,3d] pyrimidine-4-one Process 1 5.25 g of 4-chlor0benzoic acid are brought to boiling by refluxing in 50 ml of thionyl chloride. The boiling is maintained till total dissolution and then for a new period of 15 minutes. The solution is evaporated to dryness under reduced pressure, the residue is taken up with 50 ml of n-hexane and after stirring is again evaporated to dryness. To the evaporation residue, 30 ml of anhydrous pyridine and 2.3 g of 2-aminonicotinamide are aded. The mixture is brought to boiling by refluxing for 48 hours. The solution is evaporated to dryness under reduced pressure, the residue is taken up with water, the pH of the aqueous phase is brought to'the value of 8 by means of sodium bicarbonate and the residue is separated by filtration, washed with water and recrystallised from a mixture of methanol-water. The collected crystals are dried for 4 hours in vacuum-drier at 120C. Production: about 3 g. Melting point: 300.5C

Elemental analysis for C H N OCI Theoretical, "/1 :C:60.60; H1313; N:l6.3 :l6.2

I Found, :C:60.75; H:3.25; N 2

EXAMPLE l3 2-(3-Sulfonamid9phenyl)-3.4-dihydro-pyrido [2,3d] pyrimidine-4-one 9 g of 2-phenyl-3.4-dihydropyrido [2,3d] pyrimidine-4-one are treated with g of chlorosulfonic acid.

The mixture is "heated for 12 hours at C. The

cooled solution is cautiously poured on ice. The aqueous phase is brought to a pH of 4-5 and the precipitate obtained is filtered. The precipitate is washed with ice water and then stirred for 2 hours in 50 ml of 25% aqueous ammoniac solution. The solution is evaporated to dryness under reduced pressure, taken up with water and made acetic. The crystals which are separated by filtration are washed with water and recrystallised from water. They are then dried in vacuum-drier at 120C for 4 hours. About 4 g of the hereinbefore mentioned compound are obtained. Melting point: 334C.

Elemental analysis for Theoretical, 7: 1 C25 Found, "/1 C:

EXAMPLE l4 2-( 3 -Chloro-4'-sulfonamidophenyl)-3 ,4-dihydropyrido [2,3d] pyrimidine 4-one This substance is obtained by the process of Example 13 but by using as starting product the 2-(4- chlorophenyl)-3,4-dihydro-pyrido [2,3d] pyrimidine- 4-one obtained according to the process of Example 12. Melting point: 343C. Elemental analysis for C H N O SCL Theoretical. Found. 71

EXAMPLE l5 2-(3-Nitropheny1)-3,4-dihydro-pyrido [2,3d] pyrimidine-4-one Process 1 7 g of 2-phenyl-3,4-dihydro-pyrido [2,3d] pyrimidine-4-one are treated with a mixture of 20 ml of fuming nitric acid and of 20 ml of concentrated sulfuric acid for 3 hours at 90C. The cooled solution is poured under stirring in 1 litre of water and brought to a pH of 7. The crystals obtained are separated by filtration and recrystallised from a mixture of acetic acid and water. Melting point: above 360C. Process 2 Identical to that of Example 8 but by using ethyl 2- (3-nitrobenzoy1) aminonicotinate. Melting point: above 360C.

Elemental analysis for C H MO Theoretical, 7? C:58.21; H:3.00; N:20.89

Found. 1C:58.45;H13.ll;N121.07

EXAMPLE l6 2-(3-Pyridyl)-4-chloro-pyrido [2,3d] pyrimidine 10 g of 2-(3'-pyridyl)-3,4-dihydro-pyrido [2,3d]

pyrimidine-4-one. obtained as described in Example 8,

v in 100 ml of phosphorus oxychloride are brought to boiling by refluxing till total dissolution. The heating is then extended for one-fourth hour. The cooled solution is then evaporated under reduced pressure till elimina- Theoretical, /r. C:59.39 H2290; N:23.08; (1:14.60 Found, C:59.46; H13.06;N:23.25;Cl1l4.68

EXAMPLE 17 2-Phenyl-4-chloropyrido [2,3d] pyrimidine 20 Obtained according to the process of Example 16 from 2-phenyl-3,4-dihydro-pyrido [2,3d] pyrimidine- 4-one. Melting point: 170C.

Elemental analysis for C H N CI Theoretical. 7c :C164.6l', H1334; N11739: Cl'1l4.67 Found, 7c 1 064.49; H1335; N11721: Cl:14.7l

EXAMPLE 1s 2-Phenyl-4-amino-pyrido [2,3d] pyrimidine 7.5 g of 2-phenyl-4-chloro-pyrido [2,3d] pyrimidine.

and 100 ml of anhydrous methanol saturated with ammoniac are heated in a closed vessel at 120C for 12 hours. The solution is evaporated to dryness under reduced pressure and the residue is recrystallised from a mixture of methanol and water. Production: 6 g. Melt- 40 ing point: 254C Elemental analysis for C H M Theoretical, 1 C:70.27; H1450; N

:25.22 :C:7().07; H:4.60; N125.08

Found, '71

EXAMPLE 19 2-(3-Pyridyl)-4-dimethylamino-pyrido [2,3d] pyrimidine 5 g of 2-(3-pyridyl)-4-chloro-pyrido [2,3] pyrimidine and ml of an ethanolic solution of 33% dimethylamine are heated in an autoclave at 80C for 1 hour. After complete cooling, the solution is evaporated under reduced pressure, the residue is taken up with water and extracted with chloroform after verification of the aqueous phase alkalinity (residue is if desired brought to pH 8-9). The extraction liquid is dehydrated on calcium chloride and evaporated under reduced pressure. After recrystallisation from a mixture of benzenepetroleum l00-l40C, 3.5 g of substance are obtained. Melting point: 165C.

Elemental analysis for C H,;.N;, Theoretical. 7: 1C266.92;H15.2l;N:27.X7 Found. 7r (16713; H:5.l9: N1Z7.9X

EXAMPLE 20 EXAMPLE 25 2-( 3 -Pyridyl )-4-diethylamino-pyrido [2,3d]

pyrimidine 2-Phenyl-4-di-n-propylamino-pyrido [2,3d] pyrimidine Obtained according to the process of Exar nple 19 but 5 5 g of 2- h 1-4 h] r-pyrido 3 pyrimidine y 2 dlethylamme F QP lnoethanoland g ofdi-n-propylamine in 100 ml of absolute eth- Becrys'tanlsatlon toluenepetrolem 100 0 Melt anol are boiled by refluxing for 8 hours. The solution P 126-5 cooled is evaporated to dryness under reduced pressure. The residue is taken up with water, the pH of the aqueous phase is verified and eventually brought to 9.

Elemental analysis for C,..H N,., Extraction is made with chloroform, the extraction liq- 3335 2? f gfgg'fif fifg'i f uid is dehydrated on calcium chloride and then evapol m rated to dryness under reduced pressure. The residue is recrystallised from a mixture of ethanol-water. Yield: EXAMPLE 21 65%. Melting point: l39.5C.

2-(3-Pyridyl)-4-piperidino-pyrido [2,3d] pyrimidine Obtained according to the process of Example 19 but 20 Elemental analysis for C H N by using a 20% piperidine solution in ethanol and by g g l fgfzg-ggf 1: refluxing for 6 hours. Recrystallisation: petrolein l00l40. Melting point: l38.5C.

25 Elemental analysis for C, H -,N EXAMPLE 6 Theoretical, /0 C:70.08; H588; N:24.04 I Found C7024 H594 M2396 2-Phenyl-4-morpholino-pyrido [2,3d] pyrimidine Prepared as described in Example 25 but by using EXAMPLE 22 morpholine. Yield: 72%. Recrystallisation: ethyl alcoh l-w t r. Meltin oi t: l90.5C. Z-Phenyl-4-dimethylamino-pyrido [2,3d] pyrimidine O a e g p n Obtained according to the process of Example 19 but by using 2-phenyl4-chloro-pyrido [2,3d] pyrimidine. I t Recrystallisation: petrolein l00l40C. Melting point: i gsgiii ii fii sl; N:l9.l6 168C Found. :C:69.72; H:5.76; M1898 Elemental analysis for C H N Theoretical. :C:7l.98; H:5.64; N:22.38 40 Found, /z :C:72.()5; H:5.72; N:22.49

EXAMPLE 27 EXAMPLE 23 2-Phenyl-4-(N-methyl-piperazino)-pyrido 2.3a 2-Phenyl-4-diethylamino-pyrido [2,3d] pyrimidine pyrimidine Obtained according to the process of Example 20 but Prepared according to the technique of Example 25 by using 2-phenyl-4-chloro-pyrido [2,3d] pyrimidine. but by using N-methylpiperazine. Recrystallisation: pe-

Recrystallisation: petrolein l00l40. Melting point: trolein l00l40. Melting point: 155C. l20C.

Elemental analysis for C,..H,,,N Elem ntal a alysis f r C H N Theoretical, 7r. C;7().8(); H2627; N:22.93 Theoretical. /r :C:75.35;H:(1.5l; N120. l3 Found. "/0 1070.67; H:fi.52; N:22.8l Found. :C:75.38;H:6.721N:20.32

EXAMPLE 24 EXAMPLE 28 2-Phen l-4- i eridinorido 2.3d rimidine y p P W i 1 W 2-Phenyl-4-pyrrol1dmo-pyrldo [2,3d] pyrimidine Prepared as the derivative described in Example 21 but by using 2-phenyl-4-chloro-pyrido [2.3d] pyrimidine. Recrystallisation: acetone-water. Melting point:

One proceeds according to the process of Example 25 but by using py'rrolidine. Recrystallisation: ethyl acetate. Melting point: 207C.

EXAMPLE 29 2-(3'-Pyridyl)-4-methoxy-pyrido [2,3d] pyrimidine 4 g of 4-chloro-2-(3-pyridyl)-pyrido [2,3d] pyrimidine are refluxed for 4 hours in 50 ml of sodium methoxide solution containing 800 mg of metal sodium. After evaporation, the residue is taken up with water and extracted with chloroform. The substance obtained by dehydratation of the extraction liquid and evaporation is recrystallised from petrolein lO-l40. Melting point for l66.5-l67C.

Elemental analysis Theoretical. 7c Found. 7:

EXAMPLE 3O 2-Phenyl-4-methoxy-pyrido [2,3d] pyrimidine Obtained according to the process of Example 29 but by using 2-phenyl-4-chloro-pyrido [2,3d] pyrimidine. Recrystallisation: petrolein lO0-l40. Melting point: l30.5C.

Elemental analysis for C H N O Theoretical, A C:70.87; H1467; N:l7.7l Found. 71 :C:7l.07; H2473; N:l7.93

EXAMPLE 31 2-Phenyl-4-ethoxy-pyrido [2,3d] pyrimidine Obtained as the derivative described in Example 30 but by using an equivalent solution of sodium ethoxide in ethanol. Recrystallisation: petrolein l0O-l40. Melting point: 168.5C.

Elemental analysis for C H N O Theoretical, 7: C:7l.69', H:5.2 5.3

EXAMPLE 32 2-Phenyl-3-ethyl-3,4-dihydro-pyrido [2,3d] pyrimidine-4-one of Example 32 but by using methyl iodide. Melting point: 258.5C.

Elemental analysis for C H N O Theoretical, 7n :C:70.87'. H33I67; N: 17.71 Found. 7! :C:70.76; H:4.8l: N:l7.65

EXAMPLE 34 2-Phenyl-4-thiol-pyrido [2,3d] pyrimidine Process 1 11.2 g of 2-phenyl-3,4-dihydro-pyrido [2,3d] pyrimidine-4-one, 12.2 of phosphorus pentasulfide and 50 ml of anhydrous pyridine are boiled by refluxing for 4 hours. The solution is slowly poured, when still warm 2 and under stirring, in 200 ml of boiling water. The precipitate formed is allowed to cool and is separated. The precipitate is brought again into aqueous solution by addition of sodium carbonate, then one filters again and the substance is reprecipitated by addition of acetic acid till pH 4-5. The product obtained is recrystallised in a mixture of ethanol-water. Melting point: 2l0.5C. Process 2 A solution of potassium hydrogenosulfide (25 g) in 100 ml of ethanol and 100 ml of water, comprising 5 g of 2-phenyl-4-chloro-pyrido [2,3d] pyrimidine is brought to boiling. The refluxing is then continued for minutes. The solution cooled is neutralised with acetic acid and brought to pH 4-5. The precipitate collected on 'a filter is recrystallised from a mixture of ethanol-water. Melting point: 2l0.5C.

Analysis for C H N S Theoretical. C Found, 70 C The acute toxicity of substances acording to the invention was determined on mice by statistically calculating, according to Karber and Behrens, the lethal dose for% of animals (LD 50) on a period of 24 hours after intraperitoneal injection of different doses of the substances. The results are expressed in terms of mg of substance/kg body weight (see hereinafter Table). It will be noted that their acute toxicity is generally lower than that of papaverine in the same conditions.

The spasmolytic activity was studied on rat ileum 6 maintained in survival in a suitable medium (tyrode). The antogonistic effect of the substances is measured against contractions caused by carbachol. according to the method of cumulative curves of Van Rossum and by comparing with the effect of papaverine selected as reference substance (see also Table I).

When administrated to living animals (rat.mouse) at different doses and through different routes (peritoneal, gastric, venous, subcutaneous). the synthetised substances were also subjected to specific tests in order to show and study various pharmacological effects, namely: 7 v neuroleptic effect (catalepsy, palpebral ptose, an-

togonism against exciting effects of amphetamine): sedative hypnotic tranquillising effect (condition of animals, tonus and righting-up reflex, ataxy, potentialisation of barbituric effects, protection against convulsive effect of a cardiazol infusion) analgesic effect (warm water test on rat tail) exciting effect (behaviour observation) effect on arterial pressure (measured on anaesthetised animal) diuretic effect (water and ions) anti-inflammatory effect (oedoma caused by carragheenin).

Some substances, for example those of Examples 1 1, l5, l6 and 33, caused catalepsy and palpebral ptose. The most intensive effect was obtained with substance of Example 16, which at doses of 80, 40 and 20 mg/kg intraperitoneally (l.P.) also prevented on rat the appearance of stereotyped chewings, which are normally caused by an intravenous dose of 10 mg/kg of amphetamine (Janssen, Niemegeers and Schellekens: Arzneimittel, Forschung, 15, 104-117, 1965 and Janssen, Niemegeers, Schellekens and Lenaerts, Arzneimittel Forschung, vol. 17, pages 841-854, 1967). Said substances thus show an effect of neurolyptic type on the central nervous system.

Other substances, for example those of Examples 1, 2, 3, 5, 7, 22, 23, 30 and 32, have effects of a hypnosedative or tranquillising type. Some of said substances caused in the animal disturbances of the righting-up reflex from a slight slow-down to the complete stoppage for variable times and according to the doses administred. An ataxy and a tolerance increase against cardiazol in continuous venous perfusion were also noted. A strong potentialisation of the hypnotic effect of an oral dose of 40 mg/kg of secobarbital was demonlstrated for example by the substance of Example 2 administrated by gastric probe to a mouse (sleep time duplicated at the dose of 100 mg/kg). In the case of the substance of Example 22, some analgesy level was also remarked.

Some of synthetised substances are thus endowed with interesting pharmacological activities, more especially as their acute toxicity is often low.

In therapeutics, they could be for example used as hypno-sedative and tranquillising agents.

The synthetised substances were also tested to measure their diuretic action on rat. The animals put on a previous hydrous diet for 16 hours receive the substances by gastric intubation (1.6.) and are then placed? in metabolism cages. At regular intervals, the volumes of urines are noted and ions Cl, Na and K are deter; mined on the latter. Said results are brought back tot l g of rat weight and values obtained are compared; with those obtained, on the one hand, from control ani-[ mals and, on the other hand, from animals treated with; I

chlorothiazide and triamterene respectively, selected as reference substances (see Table ll: diuretic effect based on total urine volumes from the administration of the substance (time 0) till the moment when diuresis has reached its maximum, the data being brought back to 100 g of rat weight). Amongst the substances endowed with a diuretic action, the product of Example 8 is revealed asparticularly useful due to the intensity and the duration of its action. Its effect also appears as a strong sodium elimination while the potassium excretion is not very modified. Said results were confirmed on the dog, particularly at the dose of 1 mg/kg per 05.

In therapeutics, some of the synthetised substances could thus be used due to their diuretic effect. for example in cases of oedema or arterial hypertension.

The fact that potassium excretion is not very modifled is an additional advantageous point.

Several of the synthetised substances have also shown an anti-inflammatory activity. Said action was shown on rat by the carragheenin oedema test according to Winter (injection of a 1% carragheenin suspension in the plantar pad of the rear paws of the rat). The substances studied are administred by intragastric probe 1 hour before carragheenin. Three hours after carragheenin injection, the swelling of the paws is measured by means of the Lence plethysmometer, the eventual reduction with respect to control rats is calculated and comparison is made with phenyl butazone' and niflumic acid, selected as reference substances.

Some ofthe synthetised substances are endowed with an anti-inflammatory activity able to be used in therapeutics, for example in the case of acute or chronic rheumatic diseases.

The effect of the synthetised substances on the arterial pressure of the rat was studied as acute experimentation. This effect is not very important. The substances of Examples 23, 25 and 29 decrease the basic arterial pressure, while the substance of Example 19 has additionally adrenolytic effects.

TABLE 1 Example, n LDSO mg/kg(l.P.) Spasmolytic aitlion, conc.

1 450 l0 2 600 24 3 550 0 4 550 22 5 550 l7 7 550 5 8 367 4 9 500 l4 10 500 10 l l 450 l4 l2 l3 I3 550 7 l5 550 6 I6 88 6 I7 200 20 I8 I34 4 22 92 l l 23 I25 16 24 433 22 25 267 4 26 I08 13 27 l4 28 367 40 l 30 I34 I5 31 4 32 300 6 33 200 2 34 467 24 papaverine base 158 40 TABLE II Example n Dose. mg/kg(l.G.) Time, hrs. Diuretic effect.

l 5 0-32 l 4 10.0 0-24 210 6 2.50 0-8 0-8 525 8 l 25 :0-24 550 0-32 540 9 l0.0 0-32 420 10 10.0 0-32 320 TAB LE 11 Co ued.

Example n Dose, m g /l g(1.(}.) Time, hrs Diuretic effect,%

l3 10.0 -8 150 l4 10.0 0-8 170 I6 2.50 0-32 205 I8 l0.0 0-8 255 22 l0.0 O-8 235 23 l iQ 0 8 205 24 5.0 O-8 180 26 5.0 0-24 I65 30 5.0 0-32 155 3] 2.50 0-24 155 32 1.25 0-24 I75 33 2.50 O-32 260 34 L25 0-8 220 Chlorothiazidc 2.50 0-32 285 Triamterene 2.50 0-8 I90 l0.0 0-24 235 Controls 100 The numbers given in the first column of each of said Tables correspond to preparation examples of products of the invention, given hereinbefore.

The present invention has also for its object preparations intended to be parenterally administred,

including the pulmonary or branchial ways, for exam ple as aerosol.

The solid compositions for oral use can be prepared by mixing one or more substances according to the invention, for example with milk sugar, powder sugar, starch, talc, and with products intended to delay or extend the effects, for example cellulose acetophthalate, glyceryl stearates, ion exchange resins.

The suppositories can be prepared by incorporating one or more substances according to the invention with cocoabutter for example, or with any other suitable substance, such as mono-, diand triglycerides of saturated fatty acids.

The liquid compositions can be prepared for example by dissolving, suspending or emulsifying, at the time of the preparation or directly before administration, one or more substances according to the invention and moreover any other product the presence of which is considered as desirable or necessary, such as for example preservative agents, such as methyl and propyl phydrozybenzoates, thickeners and emulsifiers such as cellulose derivatives and polyoxyethylene sorbitan esters. sweetening and flavouring agents such as sugar, saccharin, sorbitol, natural or synthetic oils, isotonising agents such as sodium chloride, or buffers such as sodium phosphates, in distilled water, in other acceptable hydroxylated liquids, such as ethanol, glycerin, some glyeols, in mixtures of said solvents or in pharmaceutically acceptable oils. 7 v

We claim: 7 W v V V H l. A substituted derivative of pyrido (2,3d) pyrimidine, having the formula:

wherein R represents a pyridyl, phenyl. chlorophcnyl. sulfonamidophenyl. sulfonamidochlorophenyl or nitrophenyl radical; R represents a halogen. an alkoxy radical of l to 5 carbon atoms, an amino radical provided that R- is different from a 3-pyridyl radical. an alkylamino radical with l to 5 carbon atoms. a dialkylamino radical in which the alkyl radicals comprise l to 5 carbon atoms respectively, a morpholino. piperidino or pyrrolidino radical. a N-alkylpiperazino radical in which the alkyl radical comprises l to 5 carbon atoms. or an 0x0 or thio radical; and R is nil when R is a monovalent radical, or hydrogen (except when R, is 0x0 and R is phenyl) or an alkyl radical having 1 to 5 carbon atoms.

2. A substituted derivative of pyrido (2,3d) pyrimidine, having the formula:

wherein R is an amino radical or an alkyl or dialky] amino radical where the alkyl group has from 1 to 5 carbon atoms; R is phenyl; and R is hydrogen or an alkyl radical having l to 5 carbon atoms.

3. 2-(3'-pyridyl)-4-diethylamino-pyrido (2,3d) Pyrimidine.

4. 2-phenyl-4-diethylamino-pyrido (2,3d) pyrimidine.

5. 2-phenyl-4-dimethylamino-pyrido (2,3d) pyrimidine.

6. 2-phenyl-4-pyrrolidino-pyrido (2,3d) pyrimidine.

7. 2-phenyl-4-(N-methyl-piperazino)-pyrido (2,3d) pyrimidine.

8. 2-phenyl-4-piperidino-pyrido (2,3d) pyrimidine.

9. 2-(3-pyridyl)-3,4-dihydro-pyrido (2,3d) py imidine-4-one.

l0. 2-phenyl-3-ethyl-3 ,4-dihydro-pyrido (2,3d) pyrimidine-4-one.

l l. 2-phenyl-3-methyl-3 ,4-dihydro-pyrido (2,3d)

pyrimidine-4-one.

l2. 2-(4-pyridyl)-3,4-dihydro-pyrido(2,3d) pyrimidine-4-one.

l3. 2-(2-pyridyl-3,4-dihydro-pyrido (2,3d) pyrimidine-4-one.

l4. 2-(3-chloro-4-sulfonamidophenyl)-3,4-dihydropyrido (2,3d) pyrimidine-4-one.

l5. 2-(3-sulfonamidophenyl)-3,4-dihydro-pyrido (2,3d) pyrimidine-4-one.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENTNQ 3,873,545

0mm March 25, 1975 'l ;\-E :TOR(S) Jean P. Osselaere and Charles L. Lapiere it is certified that em: appears r he above-identified patent and that said Letters Fate. hereby corrected as shown beiow: Q

Column 1 line 51 "ro" should read or Column 2, change "COOAlkyla" to -COOAlkyl-- in Formula IV;

. Column 3, line 68, change var'rying to --var"ying--;

Columnl5, line 34, change slowclown" to "slowing-down";

Column 17, line 52, change hydrozybenzoaces to -hydroxybenzoates;

Column 18, line 14, change 3wpyridyl" to -3'pyridyl-;

Column 18, claim 9, change 3-pyridyl" to -3'pyridyl-;

, Column 18, claim 12, change (4-pyridyl)" to --(4'pyridyl)-;

Column 18, claim 13, change "(Z-pyridyl)" to (2'-pyridyl);

. Column 18, claim 14, -change "(S-chloro-4" to --(8'chloro.4

Column 18, claim 15 change "3-" to --3'- Signed and Scaled this D twenty-eight Day Of October 1975 [SEAL] Attest:

RUTH C. MASON c. MARSHALL DANN Arresting ()ffile Commissioner oj'latenrs and Trademarks 

1. A SUBSTITUTED DERIVATIVE OF PYRIDO (2,3D) PYRIMIDINE, HAVING THE FORMULA:
 2. A substituted derivative of pyrido (2,3d) pyrimidine, having the formula:
 3. 2-(3''-pyridyl)-4-diethylamino-pyrido (2,3d) pyrimidine.
 4. 2-phenyl-4-diethylamino-pyrido (2,3d) pyrimidine.
 5. 2-phenyl-4-dimethylamino-pyrido (2,3d) pyrimidine.
 6. 2-phenyl-4-pyrrolidino-pyrido (2,3d) pyrimidine.
 7. 2-phenyl-4-(N-methyl-piperazino)-pyrido (2,3d) pyrimidine.
 8. 2-phenyl-4-piperidino-pyrido (2,3d) pyrimidine.
 9. 2-(3-pyridyl)-3,4-dihydro-pyrido (2,3d) pyrimidine-4-one.
 10. 2-phenyl-3-ethyl-3,4-dihydro-pyrido (2,3d) pyrimidine-4-one.
 11. 2-phenyl-3-methyl-3,4-dihydro-pyrido (2,3d) pyrimidine-4-one.
 12. 2-(4-pyridyl)-3,4-dihydro-pyrido(2,3d) pyrimidine-4-one.
 13. 2-(2-pyridyl-3,4-dihydro-pyrido (2,3d) pyrimidine-4-one.
 14. 2-(3-chloro-4-sulfonamidophenyl)-3,4-dihydro-pyrido (2,3d) pyrimidine-4-one.
 15. 2-(3-sulfonamidophenyl)-3,4-dihydro-pyrido (2,3d) pyrimidine-4-one. 